This is a new project that builds upon our combined expertise in ErbB signaling and molecular imaging. We have discovered that Lrigl1 a pan-ErbB inhibitor, marks a novel, largely quiescent population of colonic stem cells. Using Lrig1-CreERT2;Apcflox/+ mice, we have developed a robust, highly tractable, clinically relevant, stem cell-derived mouse model of colon cancer. Through combined use of [18F]-FLT PET and [18F]-FDG PET, we discovered in vivo that mutant BRAF CRC cells resist BRAF inhibition through RAS-mediated activation of P13K signaling. Combined inhibition of BRAF and PI3K is highly efficacious in this setting. We propose to evaluate an innovative suite of biologically orthogonal imaging biomarkers to monitor tumor initiation, progression and response to targeted therapeutics in our Lrig1-Cre driver mouse model. We propose three Specific Aims to advance this work. Aim 1. To utilize TSPO ligand PET imaging to assess the efficacy of a novel Wnt inhibitor in a clinically relevant, stem cell-derived mouse model of colon cancer. In colonoscopy-confirmed tumors in Lrig1-CreERT2/+;Apcflox/+ mice, TSPO ligand PET will be evaluated as a metric for predicting clinical and histopathological response to VU-WS113, an allosteric activator of CK1alpha. We predict that Wnt pathway inhibition will result in therapeutic efficacy that can be predicted quantitatively by non-invasive imaging. Aim 2. To employ multimodal imaging to assess both colon cancer progression driven by cumulative mutations and responses to targeted therapeutics. The Lrig1-CreERT2/+;Apcflox/+ mouse will be used as a platform to introduce additional genetic events that commonly occur in human CRC (mutant BRAF, KRAS and loss of p53). Imaging metrics that report tumor cell fueling (glucose/glutamine uptake), steroidogenesis (TSPO expression), and DNA replication (thymidine kinase 1 (TK1) expression) will be compared over time and the results correlated to genetic events, tumor grade and stage, and responses to targeted therapeutics. Aim 3. To utilize molecular imaging to predict therapeutic response in a clinical trial that combines BRAF and PI3K inhibitors in patients with mutant BRAF CRC. Patients will be identified by SNaPshot genotyping provided through Vanderbilt's Personalized Cancer Medicine Initiative (PCMI). Serial [18F]-FLT PET will be evaluated prior to the initiation of therapy and day 15 of therapy, and these results will be compared to standard RECIST criteria.